If a drug delivery system (hereinafter also referred to as DDS) in which it can be directly administered to a diseased area by an injection device such as an injection syringe, a sufficient amount of a drug can be retained, it has a sustained release property which can release a drug for a long period of time by stopping at diseased area, and it is safe for a living body, can be utilized, it is extremely useful for the treatment of orthopedic surgery diseases such as osteoarthritis (arthrosis deformans), chronic rheumatoid arthritis, etc., and tumor, etc.
Polysaccharides derived from a living body such as hyaluronic acid (hereinafter also referred to as HA) or glycosaminoglycan (hereinafter also referred to as GAG), etc. have high biocompatibility, various DDS utilizing these polysaccharides have been proposed as of today.
For example, it has been tried to use a substance in which a drug is included in a crosslinked material by mixing a drug with crosslinked hyaluronic acid or hydrating the same for a base material of DDS or a sustained release preparation, and has been reported (Patent Literature 1, etc.). In these materials, a crosslinked HA or a cross-linked GAG and a drug form a complex by an ionic action, whereby a power to retain the drug is weak so that there is a defect that the drug is released within a short period of time when it is administered into a living body. Thus, it cannot obtain sufficient effects with regard to the use for sustained release the drug or for the DDS use to transport the drug to the objective diseased portion.
To the contrary, it has been proposed a material in which a drug is bound to the above-mentioned polysaccharides through a covalent bond, there have been proposed as of today an HA derivative in which a drug is bound to a carboxyl group of HA through an ester bond (Patent Literature 2), a polymer gel in which a drug is bound to a crosslinked alginic acid gel, etc. through a spacer and a peptide decomposable group by a covalent bond (Patent Literature 3), an HA derivative in which a drug is bound to an HA derivative such as HA or crosslinked HA, etc. through a spacer by a covalent bond (Patent Literature 4), and the like.
However, in general, it has been well known when a substance having high hydrophobicity such as a drug, etc., is introduced into a high-molecular weight polysaccharide or HA by a covalent bond, a solubility of the product is markedly lowered so that it is insoluble or semi-insoluble. When a larger amount of a drug is introduced, the product tends to be highly insoluble, whereby it becomes impossible to obtain a material having characteristics capable of injecting through an injection syringe, etc. In the above-mentioned Patent Literature 2, with regard to the HA derivative into which a drug has been introduced, it is not on the assumption to maintain hydrophilicity in view of an introduction of a drug and an amount of a carboxyl group(s) of HA to be used for internal esterification. The polymer gel of Patent Literature 3 is a material swelling by an aqueous liquid, so that it is not a material which can be injected by an injection syringe, etc., and the product into which a drug has been introduced is prepared in a form such as a sheet, a film, etc. In Patent Literature 4, there is no description about characteristics of the product into which a drug has been introduced, and in Examples, an degree of substitution of the drug by binding to a carboxyl group(s) which pertain to solubility is set to low.
As mentioned above, it has not been known DDS using HA as a base which satisfies all the conditions that it is capable of directly administering to a local portion by an injecting tool such as an injection syringe, etc., to diseased area such as a joint, internal organs, etc., it can maintain a sufficient amount of the drug, and it has a sustained release property which can release a drug for a long period of time by staying at diseased area.
On the other hand, the present inventors have proposed a photo-crosslinked hyaluronic acid utilizing a photo-crosslinked group as a hyaluronic acid gel having high hydrophilicity (Patent Literature 5).    [Patent Literature 1] JP-3107488 B    [Patent Literature 2] WO 89/10941    [Patent Literature 3] U.S. Pat. No. 5,770,229    [Patent Literature 4] WO 99/59603    [Patent Literature 5] U.S. Pat. No. 6,602,859